Some mammalian lungs can develop a relative tolerance to injury from several agents including oxidant gases (ozone, NO2, oxygen). If the mechanisms of "tolerance" are similar after exposure to these different toxic agents, then cross-tolerance should develop. We have proposed that NADPH production in the cytoplasm by the pentose pathway may protect the lung from injury. We will relate the tolerance of lungs to metabolic and enzymatic changes (including glucose-6-phosphate dehydrogenase and superoxide dismutase) and determine: 1) the effect of these agents upon different species at different ages, 2) the effect of co-existing diseases (pulmonary artery occlusion) or drugs (steroids) upon tolerance to injury, and 3) the effect of the toxic agents upon metabolism of tissue slices and the isolated perfused rat lung. Another objective is to relate lung function and response to injury with its supply of substrates (glucose, fatty acids, lactate etc). The isolated perfused lung produces large quantities of lactate and we hope to determine whether or not the function of the lung is dependent upon lactate production. We will measure the degree of pulmonary edema and the pulmonary vascular resistance in rat lungs perfused with and without specific substrates such as glucose. One of our postulates is that lung is partially dependent upon glycoysis for its energy supply.